| 1. |
- Ankner, Tobias, 1976, et al.
(författare)
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KHMDS enhanced SmI(2)-mediated reformatsky type alpha-cyanation.
- 2010
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Ingår i: Organic letters. - : American Chemical Society (ACS). - 1523-7052 .- 1523-7060. ; 12:10, s. 2210-3
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Tidskriftsartikel (refereegranskat)abstract
- A novel combination of SmI(2), KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse and highly sensitive 2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones to be isolated in yields ranging from 49 to 77%. In addition, alpha-bromoketones and esters were found to undergo equally effective alpha-cyanation.
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| 2. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Chroman-4-one and chromone based somatostatin beta-turn mimetics
- 2016
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 114, s. 59-64
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Tidskriftsartikel (refereegranskat)abstract
- A scaffold approach has been used to develop somatostatin beta-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' beta-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8-positions of the scaffolds using efficient reactions. Interestingly, this proof-of-concept study shows that 4 and 9 have K-i-values in the low mu M range when evaluated for their affinity for the sst2 and sst4 receptors. (C) 2016 Elsevier Masson SAS. All rights reserved.
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| 3. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Proline-mediated formation of novel chroman-4-one tetrahydropyrimidines
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 68:35, s. 7035-7040
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Tidskriftsartikel (refereegranskat)abstract
- Novel tricyclic N-benzylated chroman-4-one tetrahydropyrimidine derivatives have been prepared through a multi-component reaction between various 2-substituted chroman-4-one derivatives, N-methylenebenzylamine and a catalytic amount of proline under mild reaction conditions. The tricyclic structure of 1a was determined by NMR spectroscopy and confirmed by X-ray crystallography. An additional product, 2a, was isolated from the reaction mixture and its structure and conformation were determined by a combination of theoretical (Monte Carlo conformational search) and NMR-based (NOE and (3)J(HH) couplings) conformational analysis. The NMR analysis revealed one preferred geometry for 1a and 2a in CHCl3 solution. (C) 2012 Elsevier Ltd. All rights reserved.
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| 4. |
- Fridén-Saxin, Maria, 1979, et al.
(författare)
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Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:16, s. 7104-7113
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Tidskriftsartikel (refereegranskat)abstract
- A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC50 of 1.5 mu M. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
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| 5. |
- Karlsson, Isabella, et al.
(författare)
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Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity-Isosorbide-Based Bis-Epoxides
- 2023
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 36:2, s. 281-290
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bisepoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.
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| 6. |
- O'Boyle, Niamh M, et al.
(författare)
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Nature-derived epoxy resins: Synthesis, allergenicity, and thermosetting properties of pinoresinol diglycidyl ether
- 2022
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Ingår i: Toxicology and Industrial Health. - : SAGE Publications. - 0748-2337 .- 1477-0393. ; 38:5, s. 259-69
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Tidskriftsartikel (refereegranskat)abstract
- We describe a novel nature-derived epoxy resin monomer (ERM) derived from the plant lignan pinoresinol. Epoxy resins are thermosetting materials in global usage owing to their excellent technical properties such as flexibility and durability. However, their adverse health effects are often not considered and affect users of epoxy resins worldwide. Components of epoxy resin systems are strong skin sensitizers and cause allergic contact dermatitis. The reported prevalence attributable to epoxy chemicals is between 11.7 and 12.5% of all cases of occupational allergic contact dermatitis. We are committed to developing epoxy resins with reduced allergenic effect, while maintaining their excellent properties. The novel ERM, pinoresinol diglycidyl ether (PinoDGE), was synthesized in one step from pinoresinol and epichlorohydrin in 88% yield. It was not classified as a skin sensitizer in the in vivo local lymph node assay, at concentrations up to 0.17 m, as it did not cause a stimulation index >3 compared to control. Pinoresinol diglycidyl ether reacted with the model peptide AcPHCKRM in a reactivity assay and was predicted to be a skin sensitizer in the KeratinoSens assay. Preliminary cross-linking studies indicate that it has promising properties compared to commercially used ERMs. Pinoresinol diglycidyl ether could be seen as a lead compound for further development of alternative ERMs with a better safety profile based on natural and renewable sources for construction of epoxy resin polymers.
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| 7. |
- Ponting, David J., et al.
(författare)
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Development of New Epoxy Resin Monomers - A Delicate Balance between Skin Allergy and Polymerization Properties
- 2019
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 32:1, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- Epoxy resin monomers (ERMs) are used as building blocks for thermosetting polymers in applications where strong, flexible, and lightweight materials are required. Most epoxy resins are polymers of diglycidyl ether of bisphenol A (DGEBA). It is highly allergenic and causes occupational allergic contact dermatitis and contact allergy in the general population. Thus, measures to prevent exposure by protective clothing and education are not enough. This work describes a continuation of our research aiming at reducing the skin-sensitizing potency of ERMs while maintaining the ability to form polymers. Alternative ERMs were designed and synthesized whereafter the sensitizing potency was determined using the murine local lymph node assay (LLNA). The reactivity of the diepoxides toward a nucleophilic peptide was investigated, and the differences in reactivity explained using computational studies. The diepoxides were reacted with triethylenetetramine, and the formed polymers were tested for technical applicability using thermogravimetric analysis. We had previously shown that the absence of an oxygen atom in the side chains or removal of aromaticity reduced the sensitizing potency compared to that of DGEBA. Thus, a cycloaliphatic analogue 1 of DGEBA without ether oxygen in the side chains was considered promising and was synthesized. As predicted, the sensitizing potency was considerably reduced (10 times) compared to that of DGEBA. However, the technical properties of the polymer of this compound were not considered sufficient. More polar aromatic analogues were investigated, but they could not compete with our previously described ERMs regarding polymerization properties and with 1 regarding low skin sensitization properties. Development of alternative epoxy materials is a delicate balance between allergenic activity and polymerization properties. Tuning of structural properties together with investigation of polymerization conditions combined with skin sensitization studies should be used in industrial research and development. ERM 1 could be used as a lead compound for further studies of aliphatic ERMs.
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| 8. |
- Seifert, Tina, 1985, et al.
(författare)
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A scaffold replacement approach towards new sirtuin 2 inhibitors
- 2020
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 28:2
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Tidskriftsartikel (refereegranskat)abstract
- Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD(+)-dependent protein deacylases regulating the acylation state of epsilon-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.
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| 9. |
- Seifert, Tina, 1985, et al.
(författare)
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Chroman-4-one- and Chromone-based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:23, s. 9870-9888
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Tidskriftsartikel (refereegranskat)abstract
- Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Nε-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
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| 10. |
- Seifert, Tina, 1985, et al.
(författare)
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Identification of the Binding Site of Chroman-4-one Based Sirtuin 2 Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:23, s. 10794-10799
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Tidskriftsartikel (refereegranskat)abstract
- Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.
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| 11. |
- Seifert, Tina, 1985
(författare)
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Modulating Sirtuin Activity - Design, Synthesis and Evaluation of Sirtuin 2 Inhibitors
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sirtuins (SIRTs) are NAD+-dependent lysine deacetylating enzymes targeting histones and a multitude of non-histone proteins. The SIRTs have been related to important cellular processes such as gene expression, cell proliferation, apoptosis and metabolism. They are proposed to be involved in the pathogenesis of e.g. cancer, neurodegeneration, diabetes and cardiovascular disorders. Thus, development of SIRT modulators has attracted an increased interest in recent years. This thesis describes the design and synthesis of tri- and tetrasubstituted chroman-4-one and chromone derivatives as novel SIRT inhibitors. The chroman-4-ones have been synthesized via a one-pot procedure previously developed by our group. Further modifications of the chroman-4-ones using different synthetic strategies have increased the diversity of the substitution pattern. Chromones have been synthesized from the corresponding chroman-4-one precursors. Biological evaluation of these compounds has identified highly selective and potent SIRT2 inhibitors with IC50 values in the low µM range. Evaluation of selected compounds in cancer cell lines has shown an antiproliferative effect in breast cancer and lung carcinoma cells and an effect on the viability and morphology of brain tumor cells. A binding site for the SIRT2 inhibitors, i.e. the C-pocket of the NAD+ binding site, has been proposed using molecular modeling that showed to be consistent with the structure-activity relationship data. The proposed binding site has been further investigated using a photoaffinity labeling approach. For this, two photoactivatable chroman-4-ones containing either an azide or a diazirine moiety have been synthesized. The diazirine analog was a potent SIRT2 inhibitor. The light-induced incorporation of this photoprobe into SIRT2 followed by mass spectral analysis of the adducts has indicated that a stretch of eight amino acids has been labelled. The amino acids are located around the active site of SIRT2. One of the amino acids is a conserved histidine residue that is positioned at the part of the C-pocket to which the chroman-4-ones presumably bind. However, the low cross-linking yield has complicated the identification of the specific amino acid(s) modified by the probe. The chroman-4-one scaffold has also been replaced with different analogous bicyclic frameworks, e.g. quinolones, saccharins and benzothiadiazine-1,1-dioxides. Most of the new compounds were less active than the chroman-4-one based inhibitors, but some were moderately potent. Interestingly, the new compounds also possessed moderate SIRT3 inhibitory activity. Thus, cyclic sulfonamides show potential as SIRT2 inhibitors and might also be valuable for the development of SIRT3 selective inhibitors
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